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M402880200v1
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Papers In Press, published online ahead of print June 23, 2004
J. Biol. Chem, 10.1074/jbc.M402880200
Submitted on March 15, 2004
Revised on June 15, 2004
Accepted on June 23, 2004

Exogenous ganglioside GD1a enhances EGF receptor binding and dimerization

Yihui Liu, Ruixiang Li, and Stephan Ladisch

Center for Cancer and Immunology Research, Children's Research Institute, Washington, DC 20010

Corresponding Author: SLadisch{at}cnmc.org

Gangliosides are shed by tumor cells and can bind to normal cells in the tumor microenvironment and affect their function. Exposure of fibroblasts to exogenous gangliosides increases EGF-induced fibroblast proliferation and enhances EGF receptor (EGFR)-mediated activation of the MAP kinase signaling pathway (J. Biol. Chem., 276:42782-42792, 2001). Here we report that the EGFR itself is the target of this ganglioside effect: Preincubation of normal human dermal fibroblasts with GD1a ganglioside enhanced both EGF-induced EGFR autophosphorylation and receptor tyrosine kinase activity. The enhancement was rapid (within 30 min), not due to alteration of time kinetics of the EGFR response to EGF, and reproduced in purified GD1a-enriched cell membranes isolated from ganglioside-preincubated fibroblasts. Evaluating the initial steps underlying activation, EGF binding and EGFR dimerization, we found that GD1a enrichment of the cell membrane increased EGFR dimerization and the effective number of high affinity EGFR, without increasing total receptor protein. Unexpectedly, GD1a enrichment also triggered increased EGFR dimerization in the absence of growth factor. This resulted in enhanced activation of the EGFR signal transduction cascade when EGF was added. We conclude that membrane ganglioside enrichment of normal fibroblasts (such as by tumor cell ganglioside shedding) facilitates receptor-receptor interactions (possibly by altering membrane topology), causing ligand-independent EGFR dimerization, and in turn enhanced EGF signaling.


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